المؤلفون: Andrey Kulikov, Anastasia Dmitrieva, Elena Shipaeva, Vera Batrak, Michael Zhang, Colin Guy, Mikhail Samsonov, Jeff Duan, Ran Zhang, Georgy Shipunov, Yan Lavrovsky, Jill Smith, Sergei Barbashov, Anton Chestukhin

المصدر: Frontiers in Pharmacology, Vol 12 (2021)
Frontiers in Pharmacology

مصطلحات موضوعية: PD-L1, Pharmacology, cancer immunotherapy, medicine.drug_class, Chemistry, medicine.medical_treatment, Cancer, RM1-950, Mixed lymphocyte reaction, Monoclonal antibody, medicine.disease, in vitro efficacy, Fusion protein, animal models, In vitro, Cancer immunotherapy, monoclonal antibody, In vivo, Atezolizumab, medicine, Pharmacology (medical), therapeutic agent, Therapeutics. Pharmacology, Original Research

الوصف: RPH-120 is a novel fully human anti-PD-L1 IgG1 monoclonal antibody with specifically designed Asn300Ala mutation in Fc fragment. Surface plasmon resonance assay showed that affinity of the RPH-120 to the dimeric form of human PD-L1-Fc fusion protein was much higher than affinity to the monomeric His-tagged PD-L1. Further binding studies demonstrated that RPH-120 is able to bind to human and monkey but not mouse PD-L1. Tissue cross-reactivity study showed good comparability of human and Cynomolgus monkeys tissue staining. Bioactivity was assessed using mixed lymphocyte reaction assay. This study revealed that RPH-120 was able to activate T cells preventing PD1/PD-L1 interaction. Antitumor efficacy was analyzed in HCC-827 lung cancer xenografts in humanized CD34+ mice at three dosage levels: 20, 80, and 200 mg/kg. RPH-120 demonstrated significant tumor growth inhibition, and this inhibition was comparable to that of atezolizumab. In a single dose toxicity, toxicokinetic and dose range finding study performed in Cynomolgus monkeys, RPH-120 was administered via intravenous (IV) bolus or 60-min IV infusion, followed by 8-weeks recovery period. An acceptable toxicokinetic profile was demonstrated and administration at doses of up to 200 mg/kg was well tolerated by all animals. In conclusion, RPH-120 revealed promising in vitro and in vivo activity and safety. RPH-120 is a potent anti-PD-L1 drug candidate for cancer immunotherapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ca5ccb0106709018fc75218482361d7dTest
https://doi.org/10.3389/fphar.2021.723038Test

المؤلفون: Surender Kharbanda, Mohanraj Dhanabal, Raghu Kalluri, Udaya L. Yerramalla, Mark Manfredi, Sergei Barbashov, W. Matthew Dickerson, Kathryn A. Holthaus, Corinne L. Reimer, Yohei Maeshima

المصدر: Journal of Biological Chemistry. 276:31959-31968

مصطلحات موضوعية: Collagen Type IV, Alkylation, Tumstatin, Angiogenesis, Molecular Sequence Data, Neovascularization, Physiologic, Apoptosis, Peptide, Autoantigens, Biochemistry, Mice, Type IV collagen, Tumor Cells, Cultured, Animals, Humans, Receptors, Vitronectin, Amino Acid Sequence, Disulfides, Vitronectin, Molecular Biology, Peptide sequence, Cells, Cultured, chemistry.chemical_classification, Extracellular Matrix Proteins, Neovascularization, Pathologic, biology, Caspase 3, Cell Cycle, Cell Biology, Peptide Fragments, Recombinant Proteins, Amino acid, Enzyme Activation, Mice, Inbred C57BL, Fibronectin, chemistry, Caspases, biology.protein, Cattle, Female, Collagen, Endothelium, Vascular, Oxidation-Reduction, Cell Division, Protein Binding

الوصف: Angiogenesis is associated with several pathological disorders as well as with normal physiological maintenance. Components of vascular basement membrane are speculated to regulate angiogenesis in both positive and negative manner. Recently, we reported that tumstatin (the NC1 domain of alpha 3 chain of type IV collagen) and its deletion mutant tum-5 possess anti-angiogenic activity. In the present study, we confirm that the anti-angiogenic activity of tumstatin and tum-5 is independent of disulfide bond requirement. This property of tum-5 allowed us to use overlapping synthetic peptide strategy to identify peptide sequence(s) which possess anti-angiogenic activity. Among these peptides, only the T3 peptide (69-88 amino acids) and T7 peptide (74-98 amino acids) inhibited proliferation and induced apoptosis specifically in endothelial cells. The peptides, similar to tumstatin and the tum-5 domain, bind and function via alpha(v)beta(3) in an RGD-independent manner. Restoration of a disulfide bond between two cysteines within the peptide did not alter the anti-angiogenic activity. Additionally, these studies show that tumstatin peptides can inhibit proliferation of endothelial cells in the presence of vitronectin, fibronectin, and collagen I. Anti-angiogenic effect of the peptides was further confirmed in vivo using a Matrigel plug assay in C57BL/6 mice. Collectively, these experiments suggest that the anti-angiogenic activity of tumstatin is localized to a 25-amino acid region of tumstatin and it is independent of disulfide bond linkage. Structural features and potency of the tumstatin peptide make it highly feasible as a potential anti-cancer drug.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7f710456c4c17875a327483add3fc0a0Test
https://doi.org/10.1074/jbc.m103024200Test